Pain is the most common symptom for which patients seek medical advice and treatment Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed., 1996). The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to these harmful stimuli are known as “nociceptors”. Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities.
Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12: 372-379, 2002) to pain processing.
The lipophillic vanilloid, Capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VR1 now known as TRPV1) (Caterina M J, et. al., Science, Apr. 14; 288 (5464): 306-13, 2000). Capsaicin is the main pungent component in hot pepper. Hot pepper has been used historically not only as a spice, but also as a traditional medicine in the treatment of gastric disorders orally, and applied locally for the relief of pain and inflammation. CAP has a wide spectrum of biological actions and not only exhibits effects on the cardiovascular and respiratory systems, but also induces pain and irritancy on local application. CAP, however, after such induction of pain induces desensitization, both to CAP itself and also to other noxious stimuli, thereby stopping the pain. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of VR1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Based on this property, CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are either used or are under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorders (Wriggleworth and Walpore, Drugs of the Future, 23: pp 531-538, 1998).
VR1 is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VR1 in various systems are not properly understood at this time. An increasing number of animal studies have revealed the possible involvement of VR1 receptors in a number of pathologies. Based on this information VR1 is now being considered as a molecular target for various indications such as migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease and inflammatory diseases such as pancreatitis, and in respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, and in non specific disorders such as fervescence, retinopathy, muscle spasms, emesis, dyskinesias and depression. Specifically VR1 antagonists are likely to be useful in multiple sub-types of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g., post herpetic neuralgia, trigeminal neuralgia, and in pain due to diabetic neuropathy, dental pain as well as cancer pain. Additionally, VR1 antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritis or osteoarthritis. VR1 antagonists hold potential benefit in diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.
One class of natural and synthetic compounds that modulate the function of vanilloid Receptor (VR1) have been characterized by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group and the same have been widely studied and is extensively reviewed by Szallasi and Blumberg (The Am. Soc. for Pharmacology and Experimental Therapeutics, Vol. 51, No. 2, 1999).
Various vanilloid agonists and antagonists have been developed for the treatment of pain; the agonists work through desensitizing the receptor while antagonists block its stimulation by (patho) physiological ligands. The first antagonist Capsazepine was developed by Novartis. There are other VR1 antagonists, which are at the preclinical stage, for example, Amore Pacific's PAC-20030, Neurogen's BCTC, Abbott's A-425619 and Amgen's AMG-9810.
European Publication No. 0 462 761 discloses certain fused compounds having the formula:
which are potassium channel activators and a method of using them as antiischemic and/or anti-arrhythmic agents. PCT Publication No. WO 2005/075463 describes certain benzopyran derivatives as potassium channel activators. European Patent Publication No. 0 587 180 discloses certain benzofused derivatives for use in the treatment of ischemic conditions and arrythmia. European Patent Publication No. 0 747 374 discloses compounds having the formula:
as potassium channel activators. PCT Publication No. WO 98/045542 discloses chroman derivatives for the treatment of cardiac insufficiency.
PCT Publication No. WO 2003/080578 discloses heteroaromatic ureas as vanilloid receptor (VR1) modulators, in particular antagonists, for treating pain and/or inflammation. PCT Publication No. WO 2005/007652 describes substituted quinolin-4-yl-amine analogues useful in the treatment of conditions related to capsaicin receptor activation. PCT Publication No. WO 05/009977 discloses substituted pyrmidinyl-4-yl-amine analogues used to modulate vanilloid receptor activity. Other vanilloid receptor modulating compounds are disclosed in U.S. Pat. Nos. 6,933,311 and 6,939,891; and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 04/035533, 04/103281, 04/108133 and 04/111009.
In efforts to discover better analgesics for the treatment of both acute and chronic pain, and to develop treatments for various neuropathic pain states, there still exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by vanilloid receptors.